Conventional means for delivering pharmaceutical and therapeutic agents to mammals often are severely limited by chemical or physical barriers or both, which are imposed by the body. Oral delivery of many biologically-active agents would be the route of choice if not for the presence of chemical and physicochemical barriers such as extreme pH in the gut, exposure to powerful digestive enzymes, and impermeability of gastrointestinal membranes to the active ingredient. Among the numerous pharmacological agents which are known to be unsuitable for oral administration are biologically active peptides and proteins, such as insulin. These agents are rapidly destroyed in the gut by acid hydrolysis and/or by proteolytic enzymes.
Prior methods for orally administering vulnerable pharmacological agents have relied on co-administration of adjuvants (e.g. resorcinols and non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether) to artificially increase the permeability of the intestinal walls; and co-administration of enzymatic inhibitors (e.g. pancreatic trypsin inhibitor, diisopropylfluorophosphate (DFF) and trasylol) to avoid enzymatic degradation. Liposomes as drug delivery systems for insulin and heparin have also been described. See, for instance, U.S. Pat. No. 4,239,754; Patel et al. (1976) FEBS Letters Vol. 62, page 60; and Hashimoto et al. (1979) Endocrinol. Japan, Vol. 26, page 337. The broader use of the aforementioned methods, however, as drug delivery systems are precluded for reasons which include: (1) the use of toxic amounts of adjuvants or inhibitors; (2) narrow range of low MW cargoes; (3) poor stability of the system and inadequate shelf life; (4) difficulty in manufacturing; and (5) the failure of the method to adequately protect the active ingredient or promote its absorption.
More recently, artificial amino acid polymers or proteinoids forming microspheres have been described for encapsulating pharmaceuticals. For example, U.S. Pat. No. 4,925,673 (the '673 patent), the disclosure of which is hereby incorporated by reference in its entirety, describes such microsphere constructs as well as methods for their preparation and use. The proteinoid microspheres of the '673 patent are useful for encapsulating a number of active agents, however the preparation methods result in a complex mixture of high molecular weight (MW) (&gt;1000 daltons) and low MW (.ltoreq.1000 daltons) peptide-like polymers which are difficult to separate and yield relatively small amounts of the low MW microsphere-forming fraction. Thus, there is a need in the art for a simple and inexpensive delivery system which is simple to prepare and which can encapsulate a broad range of active agents such as proteinaceous drugs.